Intracellular oxidation of dipeptides. Base-promoted elimination from N-halodipeptides to 2-[N-alkyl-N-(2-N-alkylimino-2-alkylethanoyl)amino]-2,2-dialkylethanoic acids

One of the possible ways of intracellular oxidation of peptides is via the formation of the corresponding (N-X)-dipeptides, that then undergo base-pro moted elimination to yield intermediate 2- [N-alkyl-N-(2-N-alkylimino-2-alk ylethanoyl)amino]-2,2-dialkylethanoic acids, which subsequently hydrolyze. Such an elimination process is general-base catalyzed, with Bronsted beta v alues ranging from 0.26 to 0.31, which suggests an essentially constant deg ree of proton transfer at the TS. For (N-X)-dipeptides, the ratio k(N-Br)/k (N similar to Cl) ranges from 2.5 to 15, suggesting a structural dependence of the degree of N-X bond breaking at the TS. The values of beta and k(N-B r)/k(N-Cl) support a concerted asynchronous A(xh)D(H)D(N) mechanism, its TS changing from reactant-like to slightly nitrenium-like depending on the st ructure of the starting dipeptide. As a consequence of the antiperiplanarit y requirements of the reaction, the steric interaction between the leaving group and the substituent on the C bearing the H to be eliminated controls the reaction rate. Such steric interaction is rather important, as indicate d by the steric crossed-interaction coefficient (p(ssy ') = 0.33). Semiempi rical calculations show that bulky substituents in the vicinity of the reac tion center imply additional energy requirements for the system to achieve the antiperiplanarity needed at the TS for the reaction to proceed. From th e observations reported it follows that (N-X)-dipeptides lose their oxidizi ng power more readily than analogous (N-X)-amino acids or (N-X)-amines, ope ning a possible pathway to lessen intracellular halogen-based oxidative str ess.